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  • Review Article
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Homeostatic chemokine receptors and organ-specific metastasis

Nature Reviews Immunology volume 11, pages 597–606 (2011)Cite this article

Subjects

Key Points

  • Homeostatic chemokines are expressed in certain tissues constitutively and direct cell recruitment under resting conditions.

  • These homeostatic chemokines define 'cellular highways' that guide cells to specific organs in the body.

  • Evidence that homeostatic chemokines determine metastatic destinations has come from mouse models, in which blocking certain homeostatic chemokine receptors blocks metastasis, and from retrospective human studies, in which the expression of a chemokine receptor is associated with metastasis to a given organ and/or poor prognosis.

  • Several homeostatic chemokine receptors have been associated with metastasis. CXC-chemokine receptor 4 (CXCR4) is the most widely expressed chemokine receptor in many cancers and probably mediates metastasis to the lung, liver, brain and bone marrow.

  • CC-chemokine receptor 7 (CCR7) probably determines metastasis to lymph nodes, and CCR9 mediates rare metastases to the small intestine when expressed in some melanoma cases.

  • There are many other ways in which chemokines can affect cancer progression. For example, chemokines can promote angiogenesis, promote growth of metastatic cells in their new 'niche' and inhibit the immune system from developing strong antitumour immune responses.

Abstract

It has been 10 years since the role of a chemokine receptor, CXCR4, in breast cancer metastasis was first documented. Since then, the field of chemokines and cancer has grown significantly, so it is timely to review the progress, analyse the studies to date and identify future challenges facing this field. Metastasis is the major factor that limits survival in most patients with cancer. Therefore, understanding the molecular mechanisms that control the metastatic behaviour of tumour cells is pivotal for treating cancer successfully. Substantial experimental and clinical evidence supports the conclusion that molecular mechanisms control organ-specific metastasis. One of the most important mechanisms operating in metastasis involves homeostatic chemokines and their receptors. Here, we review this field and propose a model of 'cellular highways' to explain the effects of homeostatic chemokines on cancer cells and how they influence metastasis.

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Figure 1: The human body contains 'cellular highways' through which cells travel to reach different sites or organs in the body.
Figure 2: Tumours can evade the immune system by exploiting the chemokine system.

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References

  1. Zlotnik, A., Yoshie, O. & Nomiyama, H. The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol. 7, 243 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Soria, G. et al. Concomitant expression of the chemokines RANTES and MCP-1 in human breast cancer: a basis for tumor-promoting interactions. Cytokine 44, 191–200 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gerber, P. A., Hippe, A., Buhren, B. A., Muller, A. & Homey, B. Chemokines in tumor-associated angiogenesis. Biol. Chem. 390, 1213–1223 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Fan, L., Reilly, C. R., Luo, Y., Dorf, M. E. & Lo, D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J. Immunol. 164, 3955–3959 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Muller, G., Reiterer, P., Hopken, U. E., Golfier, S. & Lipp, M. Role of homeostatic chemokine and sphingosine-1-phosphate receptors in the organization of lymphoid tissue. Ann. NY Acad. Sci. 987, 107–116 (2003). A good review documenting the role of chemokine receptors in lymphomagenesis.

    Article  PubMed  Google Scholar 

  7. Kabashima, K. et al. CXCL12–CXCR4 engagement is required for migration of cutaneous dendritic cells. Am. J. Pathol. 171, 1249–1257 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jang, M. H. et al. CCR7 is critically important for migration of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 176, 803–810 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Britschgi, M. R., Link, A., Lissandrin, T. K. & Luther, S. A. Dynamic modulation of CCR7 expression and function on naive T lymphocytes in vivo. J. Immunol. 181, 7681–7688 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Hardtke, S., Ohl, L. & Forster, R. Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help. Blood 106, 1924–1931 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Lopez-Giral, S. et al. Chemokine receptors that mediate B cell homing to secondary lymphoid tissues are highly expressed in B cell chronic lymphocytic leukemia and non-Hodgkin lymphomas with widespread nodular dissemination. J. Leukoc. Biol. 76, 462–471 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Ohl, L. et al. Cooperating mechanisms of CXCR5 and CCR7 in development and organization of secondary lymphoid organs. J. Exp. Med. 197, 1199–1204 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen, S. C. et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J. Immunol. 168, 1001–1008 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Scimone, M. L. et al. CXCL12 mediates CCR7-independent homing of central memory cells, but not naive T cells, in peripheral lymph nodes. J. Exp. Med. 199, 1113–1120 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wengner, A. M. et al. CXCR5- and CCR7-dependent lymphoid neogenesis in a murine model of chronic antigen-induced arthritis. Arthritis Rheum. 56, 3271–3283 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Gossens, K. et al. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J. Exp. Med. 206, 761–778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vicari, A. P. et al. TECK: a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development. Immunity 7, 291–301 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Johansson-Lindbom, B. & Agace, W. W. Generation of gut-homing T cells and their localization to the small intestinal mucosa. Immunol. Rev. 215, 226–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Walters, M. J. et al. Characterization of CCX282-B, an orally bioavailable antagonist of the CCR9 chemokine receptor, for treatment of inflammatory bowel disease. J. Pharmacol. Exp. Ther. 335, 61–69 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Homey, B. et al. CCL27–CCR10 interactions regulate T cell-mediated skin inflammation. Nature Med. 8, 157–165 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Morteau, O. et al. An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation. J. Immunol. 181, 6309–6315 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Doitsidou, M. et al. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111, 647–659 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Knaut, H., Werz, C., Geisler, R. & Nusslein-Volhard, C. A zebrafish homologue of the chemokine receptor Cxcr4 is a germ-cell guidance receptor. Nature 421, 279–282 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Cui, K. et al. The CXCR4–CXCL12 pathway facilitates the progression of pancreatic cancer via induction of angiogenesis and lymphangiogenesis. J. Surg. Res. 26 Mar 2010 (doi:10.1016/j.jss.2010.03.001).

    Article  CAS  Google Scholar 

  27. Steinberg, M. & Silva, M. Plerixafor: a chemokine receptor-4 antagonist for mobilization of hematopoietic stem cells for transplantation after high-dose chemotherapy for non-Hodgkin's lymphoma or multiple myeloma. Clin. Ther. 32, 821–843 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Mahabaleshwar, H., Boldajipour, B. & Raz, E. Killing the messenger: the role of CXCR7 in regulating primordial germ cell migration. Cell Adh. Migr. 2, 69–70 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Valentin, G., Haas, P. & Gilmour, D. The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b. Curr. Biol. 17, 1026–1031 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Ehtesham, M., Mapara, K. Y., Stevenson, C. B. & Thompson, R. C. CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett. 274, 305–312 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Raz, E. & Mahabaleshwar, H. Chemokine signaling in embryonic cell migration: a fisheye view. Development 136, 1223–1229 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Thelen, M. & Thelen, S. CXCR7, CXCR4 and CXCL12: an eccentric trio? J. Neuroimmunol. 198, 9–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Dambly-Chaudiere, C., Cubedo, N. & Ghysen, A. Control of cell migration in the development of the posterior lateral line: antagonistic interactions between the chemokine receptors CXCR4 and CXCR7/RDC1. BMC Dev. Biol. 7, 23 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Liles, W. C. et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102, 2728–2730 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I. & Littman, D. R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Minami, E., Laflamme, M. A., Saffitz, J. E. & Murry, C. E. Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation 112, 2951–2958 (2005).

    Article  PubMed  Google Scholar 

  37. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001). This study identified a role for chemokines in metastasis, specifically in breast cancer metastasis to the lung.

    Article  CAS  PubMed  Google Scholar 

  38. Williams, S. A. et al. Multiple functions of CXCL12 in a syngeneic model of breast cancer. Mol. Cancer 9, 250 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Darash-Yahana, M. et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 18, 1240–1242 (2004). This study describes a correlation between high CXCR4 expression and tumour growth and metastasis in prostate cancer.

    Article  CAS  PubMed  Google Scholar 

  40. Arya, M. et al. The importance of the CXCL12–CXCR4 chemokine ligand–receptor interaction in prostate cancer metastasis. J. Exp. Ther. Oncol. 4, 291–303 (2004).

    CAS  PubMed  Google Scholar 

  41. Su, L. et al. Differential expression of CXCR4 is associated with the metastatic potential of human non-small cell lung cancer cells. Clin. Cancer Res. 11, 8273–8280 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Phillips, R. J. et al. The stromal derived factor-1/CXCL12–CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. Am. J. Respir. Crit. Care Med. 167, 1676–1686 (2003).

    Article  PubMed  Google Scholar 

  43. Speetjens, F. M. et al. Nuclear localization of CXCR4 determines prognosis for colorectal cancer patients. Cancer Microenviron. 2, 1–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Zhao, B. C. et al. CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma. World J. Gastroenterol. 17, 2389–2396 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ying, J., Xu, Q., Zhang, G., Liu, B. & Zhu, L. The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med. Oncol. 1 Jun 2011 (doi:10.1007/s12032-011-9990-0).

    Article  PubMed  CAS  Google Scholar 

  46. Savarin-Vuaillat, C. & Ransohoff, R. M. Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce? Neurotherapeutics 4, 590–601 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Terasaki, M. et al. CXCL12/CXCR4 signaling in malignant brain tumors: a potential pharmacological therapeutic target. Brain Tumor Pathol. 28, 89–97 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Wiley, H. E., Gonzalez, E. B., Maki, W., Wu, M. T. & Hwang, S. T. Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J. Natl Cancer Inst. 93, 1638–1643 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Murakami, T. et al. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res. 62, 7328–7334 (2002). This study showed that the expression of CXCR4 by the B16 cell line was sufficient for the cells to metastasize to the lung. A previous study by the same group had showed that CCR7 expression was sufficient for the cells to metastasize to the lymph nodes.

    CAS  PubMed  Google Scholar 

  50. Cunningham, H. D. et al. Expression of the C-C chemokine receptor 7 mediates metastasis of breast cancer to the lymph nodes in mice. Transl. Oncol. 3, 354–361 (2010). An elegant study showing that CCR7 expression in breast cancer cells can shift metastasis from the lung to the lymph nodes.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Schioppa, T. et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med. 198, 1391–1402 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bachelder, R. E., Wendt, M. A. & Mercurio, A. M. Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Res. 62, 7203–7206 (2002).

    CAS  PubMed  Google Scholar 

  53. Simonetti, O. et al. Potential role of CCL27 and CCR10 expression in melanoma progression and immune escape. Eur. J. Cancer 42, 1181–1187 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Homey, B. et al. Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC). J. Immunol. 164, 3465–3470 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Hla, T. & Brinkmann, V. Sphingosine 1-phosphate (S1P): physiology and the effects of S1P receptor modulation. Neurology 76, S3–S8 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Bradaric, M. J. et al. Sphingosine-1 phosphate receptor (S1p1), a critical receptor controlling human lymphocyte trafficking, is expressed in hen and human ovaries and ovarian tumors. J. Ovarian Res. 4, 4 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Amersi, F. F. et al. Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin. Cancer Res. 14, 638–645 (2008). This study documents melanoma cases that express CCR9 and shows that these tumour cells metastasize to the small intestine where CCL25 is expressed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Letsch, A. et al. Functional CCR9 expression is associated with small intestinal metastasis. J. Invest. Dermatol. 122, 685–690 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Villablanca, E. J. et al. Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nature Med. 16, 98–105 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Alfonso-Perez, M. et al. Anti-CCR7 monoclonal antibodies as a novel tool for the treatment of chronic lymphocyte leukemia. J. Leukoc. Biol. 79, 1157–1165 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Liu, F. Y. et al. NF-κB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck. Oncol. Rep. 25, 383–391 (2011).

    CAS  PubMed  Google Scholar 

  62. Emmett, M. S., Lanati, S., Dunn, D. B., Stone, O. A. & Bates, D. O. CCR7 mediates directed growth of melanomas towards lymphatics. Microcirculation 18, 172–182 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Buonamici, S. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Erreni, M. et al. Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1. Eur. J. Cancer 46, 3383–3392 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Ye, Q. H. et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nature Med. 9, 416–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Bohn, O. L. et al. Biomarker profile in breast carcinomas presenting with bone metastasis. Int. J. Clin. Exp. Pathol. 3, 139–146 (2009).

    PubMed  PubMed Central  Google Scholar 

  67. Fingleton, B. Molecular targets in metastasis: lessons from genomic approaches. Cancer Genomics Proteomics 4, 211–221 (2007).

    CAS  PubMed  Google Scholar 

  68. Furusato, B., Mohamed, A., Uhlen, M. & Rhim, J. S. CXCR4 and cancer. Pathol. Int. 60, 497–505 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Kakarala, M. & Wicha, M. S. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J. Clin. Oncol. 26, 2813–2820 (2008).

    Article  PubMed  Google Scholar 

  70. Groner, B., Vafaizadeh, V., Brill, B. & Klemmt, P. Stem cells of the breast and cancer therapy. Womens Health 6, 205–219 (2010).

    Google Scholar 

  71. Gonzalez-Sarmiento, R. & Perez-Losada, J. Breast cancer, a stem cell disease. Curr. Stem Cell Res. Ther. 3, 55–65 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. O'Hayre, M. et al. Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis. PLoS ONE 5, e11716 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Appaiah, H. et al. ITF2 is a target of CXCR4 in MDA-MB-231 breast cancer cells and is associated with reduced survival in estrogen receptor-negative breast cancer. Cancer Biol. Ther. 10, 600–614 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rhodes, L. V. et al. Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Res. 71, 603–613 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Wendt, M. K. et al. Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 25, 4986–4997 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wendt, M. K., Cooper, A. N. & Dwinell, M. B. Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 27, 1461–1471 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wislez, M. et al. High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic Kras. Cancer Res. 66, 4198–4207 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Pivarcsi, A. et al. Tumor immune escape by the loss of homeostatic chemokine expression. Proc. Natl Acad. Sci. USA 104, 19055–19060 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gao, J. Q. et al. NK cells are migrated and indispensable in the anti-tumor activity induced by CCL27 gene therapy. Cancer Immunol. Immunother. 58, 291–299 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Tessema, M. et al. Re-expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene 29, 5159–5170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010). This study found that tumours can shift their immune microenvironment from immunogenic to tolerogenic by expressing CCL21.

    Article  CAS  PubMed  Google Scholar 

  84. Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011). This study shows that hypoxic conditions induce the expression of CCL28, which subsequently recruits regulatory T cells that prevent the development of antitumour responses.

    Article  CAS  PubMed  Google Scholar 

  85. Kajiyama, H. et al. Involvement of SDF-1α/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. Int. J. Cancer 122, 91–99 (2008). This study shows that the CXCL12–CXCR4 axis augments the metastasis of ovarian cancer to the peritoneum.

    Article  CAS  PubMed  Google Scholar 

  86. Burger, J. A., Stewart, D. J., Wald, O. & Peled, A. Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev. Anticancer Ther. 11, 621–630 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Jiang, Y. P., Wu, X. H., Shi, B., Wu, W. X. & Yin, G. R. Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol. Oncol. 103, 226–233 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lu, X. & Kang, Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin. Cancer Res. 16, 5928–5935 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu, H. et al. Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. Biochem. Biophys. Res. Commun. 401, 509–515 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Ishikawa, T. et al. Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma. Oncol. Rep. 21, 707–712 (2009).

    CAS  PubMed  Google Scholar 

  92. Holm, N. T., Abreo, F., Johnson, L. W., Li, B. D. & Chu, Q. D. Elevated chemokine receptor CXCR4 expression in primary tumors following neoadjuvant chemotherapy predicts poor outcomes for patients with locally advanced breast cancer (LABC). Breast Cancer Res. Treat. 113, 293–299 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Muller, A. et al. Chemokine receptors in head and neck cancer: association with metastatic spread and regulation during chemotherapy. Int. J. Cancer 118, 2147–2157 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Uchida, D. et al. Vesnarinone downregulates CXCR4 expression via upregulation of Kruppel-like factor 2 in oral cancer cells. Mol. Cancer 8, 62 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Weaver, D. L. et al. Effect of occult metastases on survival in node-negative breast cancer. N. Engl. J. Med. 364, 412–421 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Liang, Z. et al. Inhibition of breast cancer metastasis by selective synthetic polypeptide against CXCR4. Cancer Res. 64, 4302–4308 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Li, Y. M. et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell 6, 459–469 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Milliken, D., Scotton, C., Raju, S., Balkwill, F. & Wilson, J. Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin. Cancer Res. 8, 1108–1114 (2002).

    CAS  PubMed  Google Scholar 

  101. Oda, Y. et al. Prognostic implications of the nuclear localization of Y-box-binding protein-1 and CXCR4 expression in ovarian cancer: their correlation with activated Akt, LRP/MVP and P-glycoprotein expression. Cancer Sci. 98, 1020–1026 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Akashi, T. et al. Chemokine receptor CXCR4 expression and prognosis in patients with metastatic prostate cancer. Cancer Sci. 99, 539–542 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Hirata, H. et al. CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin. Cancer Res. 13, 5056–5062 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Liang, J. J. et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 19, 2598–2604 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Marechal, R. et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br. J. Cancer 100, 1444–1451 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Marchesi, F. et al. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer Res. 64, 8420–8427 (2004). References 104–106 further substantiate the role of CXCR4 in cancer metastasis.

    Article  CAS  PubMed  Google Scholar 

  107. Franco, R. et al. Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome. Cancer Biol. Ther. 9, 423–429 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Franco, R. et al. CXCR4–CXCL12 and VEGF correlate to uveal melanoma progression. Front. Biosci. (Elite Ed.) 2, 13–21 (2009).

    Google Scholar 

  109. Scala, S. et al. Human melanoma metastases express functional CXCR4. Clin. Cancer Res. 12, 2427–2433 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. van den Oord, J. The CCR9–CCL25 axis mediates melanoma metastasis to the small intestine. Nature Clin. Pract. Oncol. 5, 440–441 (2008).

    Article  CAS  Google Scholar 

  111. Ding, Y. et al. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin. Cancer Res. 9, 3406–3412 (2003).

    CAS  PubMed  Google Scholar 

  112. Kaifi, J. T. et al. Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer. J. Natl Cancer Inst. 97, 1840–1847 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Koishi, K. et al. Persistent CXCR4 expression after preoperative chemoradiotherapy predicts early recurrence and poor prognosis in esophageal cancer. World J. Gastroenterol. 12, 7585–7590 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Takanami, I. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int. J. Cancer 105, 186–189 (2003). This retrospective study describes a highly significant correlation between CCR7 expression and metastasis to the lymph nodes in patients with lung cancer.

    Article  CAS  PubMed  Google Scholar 

  115. Katayama, A., Ogino, T., Bandoh, N., Nonaka, S. & Harabuchi, Y. Expression of CXCR4 and its down-regulation by IFN-γ in head and neck squamous cell carcinoma. Clin. Cancer Res. 11, 2937–2946 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Eisenhardt, A. et al. Expression analysis and potential functional role of the CXCR4 chemokine receptor in bladder cancer. Eur. Urol. 47, 111–117 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Kim, J. et al. Chemokine receptor CXCR4 expression in patients with melanoma and colorectal cancer liver metastases and the association with disease outcome. Ann. Surg. 244, 113–120 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Gunther, K. et al. Prediction of lymph node metastasis in colorectal carcinoma by expressionof chemokine receptor CCR7. Int. J. Cancer 116, 726–733 (2005).

    Article  PubMed  CAS  Google Scholar 

  119. Oda, Y. et al. CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: analysis within a group of patients, all of whom developed lung metastasis. Mod. Pathol. 19, 738–745 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Russell, H. V., Hicks, J., Okcu, M. F. & Nuchtern, J. G. CXCR4 expression in neuroblastoma primary tumors is associated with clinical presentation of bone and bone marrow metastases. J. Pediatr. Surg. 39, 1506–1511 (2004).

    Article  PubMed  Google Scholar 

  121. Wu, S. et al. Chemokine IL-8 and chemokine receptor CXCR3 and CXCR4 gene expression in childhood acute lymphoblastic leukemia at first relapse. J. Pediatr. Hematol. Oncol. 28, 216–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Mashino, K. et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res. 62, 2937–2941 (2002).

    CAS  PubMed  Google Scholar 

  123. Yasumoto, K. et al. Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res. 66, 2181–2187 (2006). References 122 and 123 highlight the fact that two different chemokine receptors, CXCR4 and CCR7, can play a role in the metastasis of gastric cancer.

    Article  CAS  PubMed  Google Scholar 

  124. Yang, J., Wang, S., Zhao, G. & Sun, B. Effect of chemokine receptors CCR7 on disseminated behavior of human T cell lymphoma: clinical and experimental study. J. Exp. Clin. Cancer Res. 30, 51 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

A.Z. is supported by a grant from the US National Institute of Allergy and Infectious Diseases (NIAID) (R21 AI083540-01). A.M.B. is the recipient of grant T32 AI60573 from NIAID. We apologize to those colleagues whose work could not be cited here owing to space limitations.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of California, Irvine, 92697, California, USA

    Albert Zlotnik & Amanda M. Burkhardt

  2. Department of Dermatology, Heinrich Heine Universität, Moorenstrasse 5, D-40225, Düsseldorf, Germany

    Bernhard Homey

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  1. Albert Zlotnik
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  2. Amanda M. Burkhardt
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Correspondence to Albert Zlotnik.

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Zlotnik, A., Burkhardt, A. & Homey, B. Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol 11, 597–606 (2011). https://doi.org/10.1038/nri3049

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